The present invention relates to a novel method for treating amyloid diseases, in particular Alzheimer""s disease, using carbazole compounds of Formula I, preferably carvedilol or hydroxylated derivatives of carvedilol.
Amyloid diseases are characterized by the presence of extracellular ordered, but non-crystalline, protein aggregates comprised of cross-xcex2-fibril/antiparallel xcex2-sheets formed through incorrect protein folding. Amyloid is usually pathogenic. The most common clinical amyloidoses are Alzheimer""s disease, chronic inflammation, multiple myelomas, Type II diabetes and Creutzfeldt-Jacob disease. Amyloid diseases may cause cardiac problems in old age familial amyloid polyneuropathy, and may also create the need for long-term dialysis. A general amyloidosis inhibitor could be beneficial in treating amyloid diseases, since systemic amyloid formation is reversible, and existing amyloid deposits may be resorbed, once the rate of deposition is slowed or halted.
Alzheimer""s disease (AD) is the most common cause of dementia in old age, and afflicts 5-10% of all individuals over the age of 65 years. Characteristic changes in the brain include senile plaques, neurofibrillary tangles, and the degeneration and loss of neurons. Senile plaques are located extracellularly and contain deposits of fibrillar xcex2-amyloid, the most important component of which is the xcex2A4 peptide. Aggregated forms of xcex2A4 are toxic to cultured neurons in vitro [L. Iverson et al., Biochem. J., 311, 1-16 (1995)], and the formation and aggregation of xcex2A4 in the brain is an essential early mediator of the pathology of AD.
Surprisingly, it has been found that carvedilol and related Formula I compounds are useful for treating amyloid diseases. In particular these compounds are useful in inhibiting the formation of the neurotoxic xcex2A4 oligomeric aggregate, and, thus, they would be useful in the treatment of Alzheimer""s disease.
The present invention provides a new method of using compounds which are dual non-selective xcex2-adrenoceptor and xcex11-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, in the treatment of amyloid diseases.
The present invention also provides a new method of treatment using compounds which are dual non-selective xcex2-adrenoceptor and xcex11-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for inhibiting the formation of the neurotoxic xcex2A4 oligomeric aggregate, in mammals, particularly in humans. In particular, the present invention provides a method using said compounds for treating Alzheimer""s disease.
This invention further provides a method for treating Alzheimer""s disease which comprises administering stepwise or in physical combination a compound of Formula I and a cognition enhancer, such as Memric.
The present invention provides a new method of using compounds which are dual non-selective xcex2-adrenoceptor and xcex11-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, in the treatment of amyloid diseases. In particular, the present invention provides a new method for inhibiting the formation of the neurotoxic xcex2A4 oligomeric aggregate using compounds which are dual non-selective xcex2-adrenoceptor and xcex11-adrenoceptor antagonists. Preferably, this invention provides a new method for inhibiting the formation of the neurotoxic xcex2A4 oligomeric aggregate, in particular in the treatment of Alzheimer""s disease, using compounds of Formula I: 
wherein:
R7-R13 are independently xe2x80x94H or xe2x80x94OH; and
A is H, xe2x80x94OH, or a moiety of Formula II: 
xe2x80x83wherein:
R1 is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
R3 is hydrogen or lower alkyl of up to 6 carbon atoms;
R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent xe2x80x94CH2xe2x80x94Oxe2x80x94;
X is a valency bond, xe2x80x94CH2, oxygen or sulfur;
Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
R5 and R6 are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a xe2x80x94CONH2xe2x80x94 group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or
R5 and R6 together represent methylenedioxy;
or a pharmaceutically acceptable salt thereof.
More preferably, the present invention provides a new method for inhibiting the formation of the neurotoxic xcex2A4 oligomeric aggregate using compounds of Formula III: 
wherein:
R1 is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
R3 is hydrogen or lower alkyl of up to 6 carbon atoms;
R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent xe2x80x94CH2xe2x80x94Oxe2x80x94;
X is a valency bond, xe2x80x94CH2, oxygen or sulfur;
Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
R5 and R6 are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a xe2x80x94CONH2xe2x80x94 group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or
R5 and R6 together represent methylenedioxy;
or a pharmaceutically acceptable salt thereof. These compounds are useful in the treatment of Alzheimer""s disease.
Most preferably, the present invention provides a new method for inhibiting the formation of the neurotoxic xcex2A4 oligomeric aggregate using a compound of Formula IV, better known as carvedilol or (1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol): 
This compound is useful in the treatment of Alzheimer""s disease.
Since Formula I compounds are amyloidosis inhibitors, these compounds would be useful not only in the treatment of Alzheimer""s disease, but they would also be useful in the treatment of chronic inflammation, multiple myelomas, Type II diabetes and Creutzfeldt-Jacob disease. Additionally, the compounds of the instant invention may be useful in treating cardiac problems in old age familial amyloid polyneuropathy, and they may also prevent the need for long-term dialysis.
Formula I compounds, of which carvedilol is exemplary, are novel multiple action drugs useful in the treatment of mild to moderate hypertension. Carvedilol is known to be both a competitive non-selective xcex2-adrenoceptor antagonist and a vasodilator, and is also a calcium channel antagonist at higher concentrations. The vasodilatory actions of carvedilol result primarily from xcex11-adrenoceptor blockade, whereas the xcex2-adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension. These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug in animals, particularly in humans. See Willette, R. N., Sauermelch, C. F. and Ruffolo, R. R., Jr. (1990) Eur. J. Pharmacol., 176, 237-240; Nichols, A. J., Gellai, M. and Ruffolo, R. R., Jr. (1991) Fundam. Clin. Pharmacol., 5, 25-38; Ruffolo, R. R., Jr., Gellai, M., Hieble, J. P., Willette, R. N. and Nichols, A. J. (1990) Eur. J. Clin. Pharmacol., 38, S82-S88; Ruffolo, R. R., Jr., Boyle, D. A., Venuti, R. P. and Lukas, M. A. (1991) Drugs of Today, 27, 465-492; and Yue, T.-L., Cheng, H., Lysko, P. G., Mckenna, P. J., Feuerstein, R., Gu, J., Lysko, K. A., Davis, L. L. and Feuerstein, G. (1992) J. Pharmacol. Exp. Ther., 263, 92-98.
The antihypertensive action of carvedilol is mediated primarily by decreasing total peripheral vascular resistance without causing the concomitant reflex changes in heart rate commonly associated with other antihypertensive agents. Willette, R. N., et al. supra; Nichols, A. J., et al. supra; Ruffolo, R. R., Jr., Gellai, M., Hieble, J. P., Willette, R. N. and Nichols, A. J. (1990) Eur. J. Clin. Pharmacol., 38, S82-S88. Carvedilol also markedly reduces infarct size in rat, canine and porcine models of acute myocardial infarction, Ruffolo, R. R., Jr., et al., Drugs of Today, supra, possibly as a consequence of its antioxidant action in attenuating oxygen free radical-initiated lipid peroxidation. Yue, T.-L., et al. supra.
According to the instant invention, compounds which are dual non-selective xcex2-adrenoceptor and xcex11-adrenoceptor antagonists, in particular the compounds of Formula I, preferably carvedilol, treat amyloid diseases. These compounds inhibit the formation of the neurotoxic xcex2A4 oligomeric aggregate, and, therefore, said compounds are useful for treating Alzheimer""s disease.
Some of the compounds of Formula I are known to be metabolites of carvedilol. Certain preferred compounds of the present invention, that is, the compounds of Formula I wherein A is the moiety of Formula II wherein R1 is xe2x80x94H, R2 is xe2x80x94H, R3 is xe2x80x94H, R4 is xe2x80x94H, X is O, Ar is phenyl, R5 is ortho xe2x80x94OH, and R6 is xe2x80x94H, and one of R7, R9, or R10 is xe2x80x94OH, are metabolites of carvedilol.
Compounds of Formula I may be conveniently prepared as described in U.S. Pat. No. 4,503,067. Reference should be made to said patent for its full disclosure, the entire disclosure of which is incorporated herein by reference.
Pharmaceutical compositions of the compounds of Formula I, including carvedilol, may be administered to patients according to the present invention in any medically acceptable manner, preferably orally. For parenteral administration, the pharmaceutical composition will be in the form of a sterile injectable liquid stored in a suitable container such as an ampoule, or in the form of an aqueous or nonaqueous liquid suspension. The nature and composition of the pharmaceutical carrier, diluent or excipient will, of course, depend on the intended route of administration, for example whether by intravenous or intramuscular injection
Pharmaceutical compositions of the compounds of Formula I for use according to the present invention may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as ethanol, polyvinyl-pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
Alternatively, these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, ethanol, and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
Dosing in humans for the treatment of disease according to the present invention should not exceed a dosage range of from about 3.125 to about 50 mg of the compounds of Formula I, particularly carvedilol, preferably given twice daily. As one of ordinary skill in the art will readily comprehend, the patient should be started on a low dosage regimen of the desired compound of Formula I, particularly carvedilol, and monitered for well-known symptoms of intolerance, e.g., fainting, to such compound. Once the patient is found to tolerate such compound, the patient should be brought slowly and incrementally up to the maintenance dose. The choice of initial dosage most appropriate for the particular patient is determined by the practitioner using well-known medical principles, including, but not limited to, body weight. In the event that the patient exhibits medically acceptable tolerance of the compound for two weeks, the dosage is doubled at the end of the two weeks and the patient is maintained at the new, higher dosage for two more weeks, and observed for signs of intolerance. This course is continued until the patient is brought to a maintenance dose.
This invention further provides a method for treating Alzheimer""s disease which comprises administering stepwise or in physical combination a compound of Formula I and a cognition enhancer, such as Memric. The compound known as Memric is [R-(Z)]-(methoxyimino)-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride. The methods for its preparation are disclosed in EP-A-0392803, WO95/31456 and WO93/17018.
The dose of Memric will vary in the usual way with the seriousness of the disorder, the weight of the sufferer, and the relative efficacy of the compound. However, as a general guide suitable daily doses below 0.01 mg/g more particularly 0.003 mg/kg and below, for example 0.0001-0.003 mg/kg, such as 0.00035-0.003 mg/kg, 0.0007-0.003 mg/kg, 0.0001-0.0007 mg/kg or 0.00035-0.002 mg/kg. Suitable unit doses to achieve such daily doses are 5, 12.5, 25, 50 or 75 g, administered twice daily and, in the case of 50 g, once daily.
It will be appreciated that the actual preferred dosages of the compounds being used in the compositions of this invention will vary according to the particular composition formulated, the mode of administration, the particular site of administration and the host being treated.
No unacceptable toxicological effects are expected when the compounds of Formula I are used according to the present invention.